A prospective cohort of HIV-infected Malawian women on Efavirenz initiating the Levonorgestrel Implant or the Depot Medroxyprogesterone Acetate Injectable

摘要 撒哈拉以南非洲（SSA）的意外怀孕率、孕产妇死亡率和围产期艾滋病毒感染率都很高。 增加使用有效的避孕措施可以减少这三种情况。左炔诺孕酮（LNG）植入物是一种 高效和可逆的避孕药，特别适合像马拉维这样的环境， 将进行研究。有时被称为“避孕药”，LNG植入物提供高达 5年的保护，不依赖于外部因素，如定期门诊或休息 卫生系统供应链。因此，LNG植入物的典型使用故障率非常低，在第一次试验中为0.1%。 年醋酸甲羟孕酮（DMPA）注射剂是最常用的 避孕药在上海然而，DMPA需要每3个月重复注射一次，导致更高的典型- 第一年的使用失败率为6%。最近的观察性研究表明， 抗逆转录病毒药物Efavirenz（EFV）可能会降低LNG植入物的避孕效果，这可能是由于 两种药物之间的药代动力学相互作用。根据这些小型研究，撒哈拉以南非洲的一些国家 考虑反对使用EFV的妇女使用植入物的政策建议。南非和美国。 已经发布了这样的指导。我们认为，在这个应用程序中，数据不足以支持 这项政策行动，并提出了一项由两部分组成的研究，旨在为供应商提供关键证据， 政策制定者。目的1将比较LNG植入物与DMPA的典型使用妊娠率 在1，420名接受EFV的HIV+女性的前瞻性队列中（710名开始LNG植入，710名开始注射）， 启动DMPA）。女性将在当地医疗机构接受其选择的避孕药后入组 并将在研究中在1个月后随访，然后每3个月随访一次，持续至少2年，最长4年。 将使用泊松模型估计植入物和DMPA使用者的妊娠发生率。边际 然后使用结构泊松模型估计植入物与DMPA相比的效果， 妊娠发生率目标2将对240名妇女进行2：1巢式病例对照研究， 队列，以确定头发中较高的EFV浓度（EFV暴露的生物标志物）是否与 LNG植入避孕失败。80例在使用LNG植入物时怀孕的女性（例） 将与160名在相同植入物使用时间后未妊娠的LNG植入物使用者进行比较 （对照）。将使用条件logistic回归评估毛发EFV与 浓度和LNG植入失败。我们还将评估作为一个“慢”EFV之间的关联 LNG植入失败的代谢者，并评估是否存在LNG浓度阈值， EFV使用者中发生植入物失效。这项研究将是研究人员在 位于查佩尔山的北卡罗来纳州大学（北卡罗来纳州）、马拉维项目和灯塔信托基金。我们将 与马拉维医学院和马拉维卫生部的成员密切合作， 实施和任何由此产生的关于在马拉维使用液化天然气植入物和EFV的政策决定。

ABSTRACT Sub-Saharan Africa (SSA) has high rates of unintended pregnancy, maternal mortality, and perinatal HIV. Increased use of effective contraception could reduce all three. The Levonorgestrel (LNG) implant is a highly-effective and reversible contraceptive that is particularly well-suited to settings like Malawi, where our research will take place. Sometimes referred to as “forgettable contraception,” the LNG implant provides up to 5 years of protection and is not dependent upon external factors such as regular clinic attendance or breaks in the health system supply chain. Thus, the LNG implant’s typical-use failure rate is very low at 0.1% in the first year. The Depot Medroxyprogesterone Acetate (DMPA) injectable is the most commonly-used contraceptive in SSA. However, DMPA requires repeat injections every 3 months, leading to a higher typical- use failure rate of 6% in the first year. Recent observational studies suggest that co-administration of the antiretroviral Efavirenz (EFV) may reduce the contraceptive efficacy of the LNG implant, possibly due to pharmacokinetic interaction between the two drugs. Citing these small studies, some countries in SSA are considering policy recommendations against use of implants for women on EFV. South Africa and the U.S. have already issued such guidance. We argue in this application that the data are not strong enough to support this policy action and propose a 2-part study designed to provide critical evidence to providers and policymakers. Aim 1 will compare the typical-use pregnancy rates of the LNG implant versus the DMPA injectable in a prospective cohort of 1,420 HIV+ women on EFV (710 initiating the LNG implant and 710 initiating DMPA). Women will be enrolled after receiving their chosen contraceptive at their local health facility and will be followed in the study after 1 month and then every 3 months for at least 2 years and up to 4 years. A Poisson model will be used to estimate pregnancy incidence among implant and DMPA users. A marginal structural Poisson model will then be used to estimate the effect of implant compared to DMPA upon pregnancy incidence. Aim 2 will study 240 women in a 2:1 nested case-control study of women from the cohort to determine if higher EFV concentrations in hair (a biomarker for EFV exposure) are associated LNG implant contraceptive failure. 80 women (cases) who become pregnant while using the LNG implant will be compared with 160 LNG implant users who were not pregnant after the same duration of implant use (controls). Conditional logistic regression will be used to assess the association between hair EFV concentrations and LNG implant failure. We will also evaluate the association between being a “slow” EFV metabolizer with LNG implant failure and assess if there is a LNG concentration threshold at which LNG implant failure occurs among EFV users. The study will be a collaboration between investigators at the University of North Carolina (UNC) in Chapel Hill, UNC Project-Malawi, and the Lighthouse Trust. We will work closely with members of the Malawi College of Medicine and the Malawi Ministry of Health to guide study implementation and any resulting policy decisions regarding the use of LNG implant and EFV in Malawi.